Methods and compositions for the treatment of neuropathic pain, tinnitus, and other disorders using R(-)-ketoprofen

ABSTRACT

Methods of treating neuropathic pain, tinnitus, and related disorders are disclosed. These methods comprise the administration of optically pure R(−)-ketoprofen. Also disclosed are pharmaceutical compositions useful in the treatment of neuropathic pain and tinnitus which comprise optically pure R(−)-ketoprofen.

1. FIELD OF THE INVENTION

[0001] The invention relates to methods of treating neuropathic pain,tinnitus, and other disorders, and to pharmaceutical compositions usefulin the treatment of neuropathic pain and tinnitus.

2. BACKGROUND OF THE INVENTION 2.1. Ketoprofen and its Isomers

[0002] Chemically, ketoprofen is 2-(3-benzoylphenyl)-propionic acid, andhas the following structure:

[0003] Racemic ketoprofen (a mixture of the R(−) and S(+) enantiomers)is sold under the tradenames Orudis® and Oruvail® for the treatment ofinflammation. Physicians' Desk Reference 52d Ed., p. 3092 (1998).Generally, ketoprofen is considered to be a nonsteroidalanti-inflammatory agent (“NSAID”). NSAIDs are believed to exhibitactivity as COX-1 or COX-2 enzyme inhibitors. Most NSAIDs are believedto cause gastrointestinal irritation.

[0004] The S(+) enantiomer of ketoprofen has long been thought topossess most, if not all, of the pharmacological activity of theracemate. See, e.g., Yamaguchi et al., Nippon Yakurigaku Zasshi.90:295-302 (1987); Abas et al., J. Pharinacol. Exp. Ther., 240:637-641(1987); and Caldwell et al., Biochem. Pharrnacol. 37:105-114 (1988).Indeed, U.S. Pat. Nos. 4,868,214, 4,962,124, and 4,927,854 each allegethat the analgesic activity of ketoprofen resides exclusively in theS(+) enantiomer.

[0005] However, U.S. Pat. No. 5,331,000 discloses the use of theoptically pure R(−) enantiomer as an antipyretic and analgesic agent totreat, with reduced gastrointestinal irritancy.

2.2. Neuropathic Pain

[0006] The effective treatment of pain requires an understanding of itsphysiology. It is well known, however, that stimuli which activate painreceptors in one tissue may not activate pain receptors in another. Forexample, pricking or cutting which causes pain in skin tissue does notcause pain in the stomach or intestine. The causes of pain in skeletalmuscle, joints, and arteries can also differ. Principles of Neurology,6^(th) ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), pp. 133-134.Consequently methods useful for relieving one type of pain are oftenless effective, or even ineffective, when applied to the alleviation ofothers.

[0007] In general, neuropathic pain is persistent and is characterizedby burning, gnawing, aching, shooting, or lancinating sensations. It isfrequently associated with hyperesthesia, hyperalgesia, allodynia, andhyperpathia, and in some cases by sensory deficit or autonomicdysfunction. Unfortunately, and unlike other types of pain, neuropathicpain tends to respond poorly to analgesic medication. Principles ofNeurology, 6^(th) ed., Adams, R. D., et al.; eds. (McGraw-Hill: 1997),p. 140.

[0008] Depending on the particular nerves involved, a particularinstance of neuropathic pain can be classified as a central orperipheral neuropathy. Central neuropathies arise from spinal cord,brainstem, thalamic, and cerebral damage or disease, while peripheralneuropathies arise from damage or disease of peripheral nerves. Specificperipheral neuropathies include, but are not limited to: thoracic outletobstruction syndromes; compression and entrapment neuropathies such asulnar nerve palsey, carpal tunnel syndrome, peroneal nerve palsey,radial nerve palsey; and Guillain-Barré syndrome. The Merk Manual, 16thed., 1518-1522 (1992).

[0009] Neuropathic, or neurogenic, pain arises from the directstimulation of nervous tissue. Neuropathic pain encompasses a widevariety of disorders involving single and multiple nerves. Theseinclude, but are not limited to, trigeminal neuralgia and disorders dueto herpes zoster, diabetes, and trauma (including causalgia); spinalarachnoiditis and spinal cord injuries; and the thalamic pain syndromeof Déjerine-Roussy. Principles of Neurology, 6^(th) ed., Adams, R. D.,et al., eds. (McGraw-Hill: 1997), p. 140.

[0010] Neuropathic pain is caused by a variety of factors including, butnot limited to: trauma caused by injury or surgical operation; tumors;bony hyperostosis; casts; crutches; prolonged cramped postures;hemorrhage into a nerve; exposure to cold or radiation;collagen-vascular disorders; metabolic diseases such as diabetes;infectious diseases such as Lyme disease and HIV; toxins such asemetine, hexobarbital barbital chlorobutanol, sulfonamides, phenytoin,nitrofurantoin, the vinca alkaloids, heavy metals, carbon monoxide,triorthocresylphosphate, orthodinitrophenol and other solvents andindustrial poisons; autoimmune reactions; nutritional deficiency, andvitamin B deficiency in particular; and metabolic disorders such ashypothyroidism, porphyria, sarcoidosis, amyloidosis, uremia anddiabetes. The Merck Manual, 16th ed., 1518 (1992).

[0011] Because so many causes of neuropathic pain exist, and because ittends to respond poorly to analgesic medication, the discovery of drugsthat safely and effectively aid in its relief has been difficult.

2.3. Tinnitus

[0012] Like neuropathic pain, tinnitus is often thought of as asubjective disorder; numerous causes have thus been postulated for it. Apatient with tinnitus typically perceives a sound in the head or theears without an evident external stimulus. Such sounds often have abuzzing, ringing, roaring, whistling, or hissing quality, or may be morecomplex and vary over time. Vesterager, V., BMJ, 314:728-31 (1997).

[0013] Tinnitus can result from nearly all ear disorders, including, butnot limited to: obstruction of the external auditory canal; infectiousprocesses such as external otitis, myrignitis, otitis media,labyrinthitis, petrositis, syphilis and meningitis; eustachian tubeobstruction; otosclerosis; middle ear neoplasms such as the glomustympanicum and glomus jugulare tumors; Meniere's disease; arachnoiditis;cerebellopontine angle tumors; cardiovascular diseases such ashypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism;hereditary sensorineural or noise-induced hearing loss; and acoustictrauma. The Merck Manual, 16th ed., 2324 (1992). Tinnitus can alsoresult from ototoxicity caused by acute intoxication or long-termadministration or exposure to salicylates, quinine and its syntheticanalogues, aminoglycoside antibiotics, diuretics, carbon monoxide, heavymetals, and other drugs or toxins. Seligmann, H., et al., Drug Safety14(3):198-212 (1996). Psychological causes have also been suggested.Vesterager, V., BMJ, 314:728-31 (1997).

[0014] The biological mechanism which causes or relates to tinnitusremains unclear. Some researchers have suggested that it may result froma decrease of the normal GABAergic inhibitory influence of neurons inthe inferior colliculus. Møller, A. R., Am. J. Otology, 18:577-585(1997). Others have argued that the disorder results from pathologicalchanges of neurons within the inner ear. See, e.g., Ehrenberger, K, andFelix, D., Acta Otolaryngol (Stockh), 115:236-240 (1995). It has alsobeen suggested that tinnitus generation might be similar to the “gatetheory” of pain. See, e.g. Murai, Kazuo, et al., Am. J. Otology13(5):454464 (1992); Sahley, T. L., et al., Ear & Hearing 17:341-353(1996); and Sahley, T. L., et al., Ear & Hearing 17:552-558 (1996).

[0015] Because its mechanism is poorly understood, the discovery ofdrugs that are effective in the treatment of tinnitus has been slow.Some researchers have alleged that administration of the localanesthetic lidocaine can reduce symptoms of the disorder, but itsalleged effectiveness is of short duration. Lyttkens, L., Scand. Audiol.Suppl. (Sweden) 26:27-31 (1986); and Mural, Kazuo, el al., Am. J Otology13(5):454464 (1992). Other drugs alleged to be somewhat effective in thetreatment of tinnitus include oxazepam, clonazepam, glutamic acid,streptomycin, and eperisone hydrochloride. Murai, Kazuo, et al., Am. JOtology 13(5):454-464 (1992). Unfortunately, these and other drugs areallegedly effective in only a few patients. More important, those drugsthat are reportedly the most effective (e.g., lidocaine, oxazepam andclonazepam) can cause a wide variety of adverse effects. These include,but are not limited to, numbness, tingling, light-headedness, blurredspeech, nausea, dermatitis, uricarial exanthema, vomiting, tremor,visual disturbance, disequilibrium, rashes, headache, diplopia,sedation, and sleepiness. Murai, Kazuo, et al., Am. J. Otology13(5):454464 (1992). There thus exists a need for a safe and effectivemethod of treating tinnitus.

3. SUMMARY OF THE INVENTION

[0016] The invention is directed to methods of treating or preventingneuropathic pain, tinnitus, and other disorders, as well aspharmaceutical compositions suitable for the treatment of neuropathicpain and tinnitus.

[0017] This invention encompasses the use of optically pureR(−)-ketoprofen for treating or preventing neuropathic pain, which isgenerally not treated by anti-inflammatory, analgesic, or antipyreticagents. Moreover, the invention encompasses the use of optically pureR(−)-ketoprofen to treat or prevent tinnitus or ringing in the ears,which has heretofore been notoriously difficult to treat with anytherapeutic agent.

3.1. Definitions

[0018] As used herein, the term “mammal” includes human. The terms“human” and “patient” are used interchangeably herein.

[0019] As used herein, the term “treating neuropathic pain” meansalleviating, ameliorating, reducing, or relieving at least one symptomof acute or chronic neuropathic pain. Symptoms of acute or chronicneuropathic pain include, but are not limited to, burning, gnawing,aching, shooting, or lancinating sensations, sensory deficit, andautonomic dysfunction.

[0020] As used herein, the term “treating tinnitus” means alleviating,ameliorating, reducing, or relieving at least one symptom of acute orchronic tinnitus. Symptoms of acute or chronic tinnitus include, but arenot limited to, the hearing of buzzing, ringing, roaring, whistling, orhissing sounds.

[0021] As used herein, the term “patient at risk of tinnitus” means apatient who is suffering from a disease or condition that is associatedwith tinnitus. Diseases or conditions associated with tinnitus include,but are not limited to: obstruction of the external auditory canal;infectious processes including external otitis, myrignitis, otitismedia, labyrinthitis, petrositis, syphilis and meningitis; eustachiantube obstruction; otoscierosis; middle ear neoplasms such as the glomustympanicum and glomus jugulare tumors; Meniere's disease; arachnoiditis;cerebellopontine angle tumors; cardiovascular diseases includinghypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism;hereditary sensorineural or noise-induced hearing loss; acoustic trauma;ototoxicity caused by acute intoxication or long-term administration orexposure to drugs or toxins including salicylates, quinine and itssynthetic analogues, aminoglycoside antibiotics, diuretics, carbonmonoxide; and heavy metals; and psychological disorders.

[0022] As used herein, the term “substantially free of its S(+)enantiomer” means that the composition contains less than about 10% byweight S(+)-ketoprofen. Preferably, the term “substantially free of itsS(+) enantiomer” means that the composition contains less than about 5%by weight S(+)-ketoprofen. Most preferably, the term “substantially freeof its S(+) enantiomer” means that the composition contains less thanabout 1% by weight of S(+)-ketoprofen. These percentages are based uponthe total amount of ketoprofen present in the composition. The terms“substantially optically pure R(−) enantiomer of ketoprofen” or“substantially optically pure R(−)-ketoprofen” and “optically pureR(−)-ketoprofen” or “optically pure R(−) enantiomer of ketoprofen” arealso encompassed by the above-described amounts.

[0023] As used herein, the term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicorganic or inorganic bases. Suitable organic bases include, but are notlimited to, lysine, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine. Suitable inorganic bases include, but are not limited to,alkaline and earth-alkaline metals such as aluminum, calcium, lithium,magnesium, potassium, sodium and zinc. 4. DETAILED DESCRIPTION OF THEINVENTION

[0024] The invention involves using optically pure R(−)-ketoprofen toeffectively treat neuropathic pain, tinnitus, and related disorders. Theinvention encompasses treating these disorders without causing adverseeffects associated with racemic ketoprofen. Adverse effects associatedwith racemic ketoprofen include, but are not limited to:gastrointestinal irritation such as dyspepsia, nausea, abdominal pain,diarrhea, constipation, flatulence, vomiting, and stomatitis; anorexia;headache; dizziness; CNS inhibition such as somnolence, malaise, anddepression; CNS excitation such as insomnia and nervousness;hypertension; palpitation; tachycardia; congestive heart failure;peripheral vascular disease, and tinnitus.

[0025] A first embodiment of the invention encompasses a method oftreating neuropathic pain in a mammal which comprises administering to amammal in need of such treatment a therapeutically effective amount ofsubstantially optically pure R(−)-ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof. Preferably, thetherapeutically effective amount of substantially optically pureR(−)-ketoprofen, or pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 1 mg and about 2000 mg, morepreferably between about 5 mg and about 1500 mg, and most preferablybetween about 10 mg and about 1000 mg. Preferably, the substantiallyoptically pure R(−)-ketoprofen comprises less than about 10% by weightS(+)-ketoprofen, more preferably less that about 5% by weightS(+)-ketoprofen, and most preferably less than about 1% by weightS(+)-ketoprofen.

[0026] This embodiment of the invention encompasses a method of treatinga central neuropathy in a mammal. Preferably, the central neuropathyarises from the damage or disease of the spinal cord, brainstem,thalamus, or cerebellum.

[0027] The first embodiment of the invention also encompasses a methodof treating a peripheral neuropathy in a mammal. Preferred peripheralneuropathies include, but are not limited to: thoracic outletobstruction syndromes; compression and entrapment neuropathies such asulnar nerve palsey, carpal tunnel syndrome, peroneal nerve palsey, andradial nerve palsey; and Guillain-Barré syndrome.

[0028] This first embodiment of the invention further encompassescompositions adapted for the treatment of a mammal suffering fromneuropathic pain which comprise a therapeutically effective amount ofsubstantially optically pure R(+ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof said amount beingsufficient to alleviate at least one symptom of neuropathic pain. Theembodiment encompasses single unit dosage forms of substantiallyoptically pure R(−)-ketoprofen which comprise from about 1 mg to about2000 mg, more preferably from about 5 mg to about 1500 mg, and mostpreferably from about 10 mg to about 1000 mg of optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof. Preferably, the substantially optically pureR(−)-ketoprofen comprises less than about 10% by weight S(+)-ketoprofen,more preferably less that about 5% by weight S(+)-ketoprofen, and mostpreferably less than about 1% by weight S(+)-ketoprofen.

[0029] Another embodiment of the invention encompasses a method oftreating or preventing tinnitus or ringing in the ear in a patient whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof. Preferably, the therapeutically effective amount ofsubstantially optically pure R(−)-ketoprofen, or pharmaceuticallyacceptable salt, solvate, or clathrate thereof, is between about 1 mgand about 2000 mg, more preferably between about 5 mg and about 1500 mg,and most preferably between about 10 mg and about 1000 mg. Preferably,the substantially optically pure R(−)-ketoprofen comprises less thanabout 10% by weight S(+)-ketoprofen, more preferably less that about 5%by weight S(+)-ketoprofen, and most preferably less than about 1% byweight S(+)-ketoprofen.

[0030] This embodiment of the invention also encompasses a method ofpreventing tinnitus or ringing in the ear in a patient at risk oftinnitus.

[0031] This embodiment of the invention further encompasses a method oftreating tinnitus or ringing in the ear associated with a disease orcondition selected from the group consisting of: obstruction of theexternal auditory canal; infectious processes including external otitis,myrignitis, otitis media, labyrinthitis, petrositis, syphilis andmeningitis; eustachian tube obstruction; otosclerosis; middle earneoplasms such as the glomus tympanicum and glomus jugulare tumors;Meniere's disease; arachnoiditis; cerebellopontine angle tumors;cardiovascular diseases including hypertension, arteriosclerosis andaneurysms; anemia; hypothyroidism; hereditary sensorineural ornoise-induced hearing loss; acoustic trauma; ototoxicity caused by acuteintoxication or long-term administration or exposure to drugs or toxinsincluding salicylates, quinine and its synthetic analogues,aminoglycoside antibiotics, diuretics, carbon monoxide, and heavymetals; and psychological disorders.

[0032] This embodiment of the invention also includes compositionsadapted for the treatment of a patient suffering from tinnitus whichcomprise a therapeutically effective amount of optically pureR(−)-ketoprofen or a pharmaceutically acceptable salt, solvate, orclathrate thereof said amount being sufficient to alleviate at least onesymptom of tinnitus. The embodiment encompasses single unit dosage formsof substantially optically pure R(−)-ketoprofen which comprise fromabout 1 mg to about 2000 mg, more preferably from about 5 mg to about1500 mg, and most preferably from about 10 mg to about 1000 mg ofoptically pure R(−)-ketoprofen, or a pharmaceutically acceptable salt,solvate, or clathrate thereof Preferably, the substantially opticallypure R(−)-ketoprofen comprises less than about 10% by weightS(+)-ketoprofen, more preferably less that about 5% by weightS(+)-ketoprofen, and most preferably less than about 1% by weightS(+)-ketoprofen.

[0033] A final embodiment of the invention encompasses compositionscomprising R(−)-ketoprofen and a pharmaceutically acceptable carrier.

4.1. Synthesis and Preparation

[0034] Racemic ketoprofen can be made by the method described in U.S.Pat. No. 3,641,127, which is hereby incorporated by reference. The R(−)enantiomer of ketoprofen can be readily obtained from the racemateusing, for example, high performance liquid chromatography (HPLC) or anoptically active resolving base. A preferred method of resolving theR(−) enantiomer is disclosed in U.S. Pat. No. 5,677,469, which isincorporated herein by reference. Other methods suitable for resolvingR(−)-ketoprofen are disclosed by, for example, U.S. Pat. Nos. 4,983,765and 4,973,745, both of which are incorporated herein by reference. See,also, Jacques, J., et al., Enantiomers, Racemates and Resolutions(Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds(McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agentsand Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre DamePress, Notre Dame, Ind., 1972).

[0035] Enzymatic biocatalytic resolution may also be used to isolate theoptically pure R(−) enantiomer from racemic ketoprofen. See, e.g., U.S.Pat. Nos. 5,057,427, and 5,077,217, both of which are incorporatedherein by reference. A preferred enzymatic method is disclosed by U.S.Pat. No. 5,457,051, which is also incorporated herein by reference.

[0036] Optically pure R(−)-ketoprofen can further be prepared from thecorresponding acrylic acid by catalytic hydrogenation using a chiralcatalyst. See, e.g., U.S. Pat. Nos. 5,198,561; 5,202,473; 5,202,474;5,233,084; and 5,097,064, all of which are incorporated herein byreference.

[0037] Pharmaceutically acceptable salts of R(−)-ketoprofen are readilymade using techniques well known to those skilled in the art. Examplesof such techniques, and the salts made therefrom, are disclosed by U.S.Pat. No. 5,808,069, which is incorporated herein by reference.

4.2. Pharmaceutical Compositions and Method of Use

[0038] The magnitude of a prophylactic or therapeutic dose ofR(−)-ketoprofen (referred to herein as the “active ingredient”) in theacute or chronic management of disease (i.e., neuropathic pain,tinnitus, or a related disorder) will vary with the severity of thecondition to be treated and the route by which the drug is administered.The dose, and perhaps the dose frequency, will also vary according tothe age, body weight, and response of the individual patient. Ingeneral, the total daily dose range of R(−)-ketoprofen is from about 1mg to about 2000 mg, in single or divided doses. Preferably, a dailydose range should be between about 5 mg and about 1500 mg, in single ordivided doses. More preferably, a daily dose range should be betweenabout 10 mg and about 1000 mg, in single or divided doses. In managingthe patient, the therapy should be initiated at a lower dose, perhapsabout 1 mg to about 200 mg, and increased up to about 1000 mg or higherdepending on the patient's global response. It is further recommendedthat infants, children, patients over 65 years, and those with impairedrenal or hepatic function, initially receive low doses, and that they betitrated based on individual response(s) and blood level(s). It may benecessary to use dosages outside these ranges in some cases as will beapparent to those skilled in the art. Further, it is noted that theclinician or treating physician will know how and when to interrupt,adjust or terminate therapy in conjunction with individual patientresponse. The terms “therapeutic amount” and “therapeutically effectiveamount” are encompassed by the above-described dosage amounts and dosefrequency schedules.

[0039] In practical use, optically pure R(−)-ketoprofen can be combinedas the active ingredient in intimate admixture with a pharmaceuticallyacceptable carrier according to conventional pharmaceutical compoundingtechniques. The pharmaceutically acceptable carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., oral, parenteral (including intravenous,subcutaneous, intrathecal, and intramuscular), transdermal, and topical.In preparing the compositions for oral dosage form, any of the usualpharmaceutical media or excipients may be employed. These include, forexample, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations such as suspensions, elixirs and solutions; or aerosols; orexcipients such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as powders,capsules, caplets, and tablets. Solid oral preparations are generallypreferred over liquid ones. Because of their ease of administration,tablets and capsules represent the most advantageous oral dosage unitforms, in which case solid pharmaceutical pharmaceutically acceptableexcipients are obviously employed. If desired, tablets may be coated bystandard aqueous or nonaqueous techniques. Preferred solid oralpreparations are tablets and capsules.

[0040] Pharmaceutical stabilizers may be used to stabilize compositionscomprising optically pure R(−)-ketoprofen, or pharmaceuticallyacceptable salts, solvates, or clathrates thereof. Acceptablestabilizers include, but are not limited to, L-cysteine hydrochloride,glycine hydrochloride, malic acid, sodium metabsulfite, citric acid,tartaric acid, and L-cystine dihydrochloride. See, e.g., U.S. Pat. Nos.5,731,000; 5,763,493; 5;541,231; and 5,358,970, all of which areincorporated herein by reference.

[0041] In addition to the common dosage forms set out above, the activeingredient (i.e., optically pure R(−)-ketoprofen) can be administered bycontrolled release means and/or delivery devices capable of releasingthe active ingredient at a rate required to maintain constantpharmacological activity for a desirable period of time. Such dosageforms provide a supply of a drug to the body during a predeterminedperiod of time and thus maintain drug levels in the therapeutic rangefor longer periods of time than conventional non-controlledformulations. Examples of controlled release pharmaceutical compositionsand delivery devices which may be adapted for the administration of theactive ingredient of the invention are described in U.S. Pat. Nos.3,847,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,749;4,687,610; 4,769,027; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,566; and 5,733,566, the disclosures of whichare incorporated herein by reference.

[0042] Pharmaceutical compositions of the invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, caplets, or tablets or aerosol sprays, each containing apredetermined amount of the active ingredient as a powder, as granules,or as a solution or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy whichinclude the step of bringing into association the active ingredient witha pharmaceutically acceptable carrier which constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with a liquidpharmaceutically acceptable carrier or a finely divided solidpharmaceutically acceptable carrier, or both, and then, if necessary,shaping the product into the desired presentation. For example, a tabletmay be prepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, disintegrating agent, and/or surface active or dispersingagent. Molded tablets may be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.Preferably, each tablet contains from about 0.5 mg to about 1000 mg ofthe active ingredient, and each cachet or capsule contains from about0.5 mg to about 2000 mg of the active ingredient, more preferably fromabout 5 mg to about 1500 mg, and most preferably between about 10 mg andabout 1000 mg.

[0043] The invention is further defined by reference to the followingexamples describing in detail the preparation of the compound andcompositions of the invention. It will be apparent to those skilled inthe art that many modifications, both to materials and methods, may bepracticed without departing from the scope of the invention.

5. EXAMPLES 5.1. Example 1 Chiral Salt Resolution of R(−)-ketoprofen

[0044] A sample of 126 g (500 mmol) of (R,S)-ketoprofen was combinedwith 800 g of methyl isobutyl ketone, heated to 40° C. and stirred untilthe mixture dissolved. The solution was treated with 74 g (500 mmol) ofcis-(1S,2R)-1-aminoindan-2-ol, mixed for 30 minutes, seeded with 20 g ofR(−)-ketoprofen cis-(1S,2R)-1-aminoindan-2-ol diastereomer salt and heldat 40° C. for 30 minutes. The mixture was-cooled to 25° C. over thecourse of 4 hours and further cooled to 15° C. over the course of hourand then held at 15° C. for 18 hours. The solids that formed werecollected by filtration and dried under vacuum to yield 86 g ofR(−)-ketoprofen cis-(1S,2R)-1-aminoindan-2-ol diastereomer with anR(−)-ketoprofen diastereomeric excess of 97%. The acid was released fromthe diastereomer salt by combining the solid with equal amounts (315 g)of ethyl acetate and aqueous (12 weight percent) sulfuric acid. Aftermixing, the aqueous phase was separated (saved for recovery ofaminoindanol) and the organic phase washed twice with equal volumes ofwater. The organic phase was evaporated under vacuum. The weight of thesolid residue was 54 g (66% yield based on available enantiomer andcorrected for added seed diastereomer salt crystals) corresponding toR(−)-ketoprofen of 97% enantiomeric excess.

5.2. Example 2 Enzymatic Resolution of R(−)-ketoprofen

[0045] A. Synthesis of Dimethylethanolamine Ester

[0046] Racemic ketoprofen (0.5 moles) was added to thionyl chloride (1.0moles) in a flask fitted with a drying tube. Dimethylformamide (0.25 ml)was added to the reaction mixture and the mixture was stirred and warmeduntil the ketoprofen dissolved and gas evolution commenced. The heat wasremoved and the mixture was stirred at room temperature for 18 hours.The thionyl chloride was removed under reduced pressure and the oilyresidue of acid chloride slowly solidified.

[0047] The acid chloride was dissolved in tetrahydrofuran (125 ml) andadded to a solution of N,N-dimethylethanolamine (1.0 moles) intetrahydrofuran (500 ml) cooled to 0° C. in a flask equipped with adrying tube. After the addition, the reaction mixture was stirred atroom temperature for 18 hours. A saturated aqueous solution of potassiumcarbonate (500 ml) was added to the reaction mixture and the resultingorganic layer was removed. The aqueous layer was extracted with diethylether (2×250 ml) and the organic layers were combined, washed with asaturated aqueous solution of sodium chloride, dried over potassiumcarbonate and the solvent removed under reduced pressure. The productwas isolated as a colorless viscous oil.

[0048] B. Quaternization of the N,N-Dimethylethanolamine Ester

[0049] The resulting N,N-dimethylethanolamine ester was dissolved indiethyl ether (500 ml) and cooled to 0° C. A solution of dimethylsulfate (0.36 moles) in diethyl ether (500 ml) was added to the cooledsolution and the resulting solution was stirred at room temperature for18 hours. The resulting solid material was removed by filtration, washedwith diethyl ether and dried under vacuum to yield theN,N,Ntrimethylethanolammonium ester of ketoprofen (ketoprofen cholineester) as a white solid.

[0050] C. Enzymatic Transesterification of the Racemic KetoprofenCholine Ester

[0051] The choline ester (0.36 moles) was dissolved in 0.2 M sodiumphosphate buffer (900 ml, pH 7.0). To this solution was added methanol(100 ml) and Protease type XXVII (3 gm) which is available commerciallyfrom Sigma Chemical Co., St. Louis, Mo. The reaction was allowed to stirgently at room temperature for 24 hours. The reaction mixture wasextracted with diethyl ether (2×250 ml) and the organic layer wasreserved. The aqueous layer was adjusted to pH 2 by the addition ofconcentrated sulfuric acid and the resulting mixture was washed withether (2×150 ml). The aqueous layer was concentrated under reducedpressure and the volume was adjusted to 900 ml by the addition of 0.2 Msodium phosphate buffer (pH 7.0). To this solution was added methanol(100 ml) and Protease type XXVII (2 gm). The reaction was allowed tostir gently at room temperature for 24 hours. The reaction mixture wasextracted with diethyl ether (2×250 ml) and this organic layer wascombined with the layer reserved from the first enzymatic reaction. Thecombined ether layers were dried over magnesium sulfate and the solventremoved under reduced pressure to leave crude R(−)-ketoprofen methylester, which was dried under vacuum.

[0052] D. Preparation of R(−)-ketoprofen

[0053] The crude ester was combined with ethanolic potassium hydroxidesolution (pH 13) and the resulting mixture was stirred for 1 hour atroom temperature.

[0054] The resulting solution was adjusted to pH 2 by the addition ofhydrochloric acid. The resulting mixture was extracted with diethylether and the combined ether solutions were dried over magnesium sulfateand the solvent removed under reduced pressure to leave crudeR(−)-ketoprofen. The crude acid was recrystallized from diethyl ether toyield R(−)-ketoprofen.

5.3. Example 3 Evaluation of Neuropathic Pain

[0055] Tight ligation of the L₅ and L₆ spinal nerves in rats can be usedto model neuropathic pain, as it produces signs of neuropathicdysesthesias, including tactile allodynia, thermal hyperalgesia andguarding of the affected paw. Such nerve ligation injury can beperformed by the method described by Kim and Chung, Pain, 50(3):355-363(1992). In this method, rats are anesthetized with halothane and thevertebrae over the L4 to S2 region are exposed. The L₁ and L₆ spinalnerves are exposed, carefully isolated, and tightly ligated with 4-0silk suture distal to the dorsal root ganglion (“DRG”). After ensuringhomeostatic stability, the wounds are sutured, and the rats allowed torecover in individual cages. Sham-operated rats are prepared in anidentical manner except that the L₁ and L₆ spinal nerves are notligated. Any rats which show signs of motor deficiency are not used inthe study.

[0056] Tactile allodynia and thermal hyperalgesia evaluations areperformed using the ligated and sham-operated rats. R(−)-ketoprofen, orother test article or control, is administered to the rats prior toperforming these evaluations.

[0057] Mechanical allodynia is determined in the manner described byChaplan et al., J. Neurosci. Methods, 53(1):55-63 (1994), wherein thepaw withdrawal threshold is determined in response to probing withcalibrated von Frey filaments. In this method, the rats are suspended incages having wire mesh floors. Von Frey filaments are appliedperpendicularly to the plantar surface of the rat's paw until it bucklesslightly, and is held for about 3 to 6 seconds. A positive response isindicated by a sharp or abrupt withdrawal of the paw. The 50% pawwithdrawal threshold is determined by a non-parametric method, as iswell known to those skilled in the art.

[0058] Thermal hyperalgesia is determined by focusing a radiant heatsource onto the plantar surface of the affected paw of nerve-ligated orsham-operated rats. When a rat withdraws its paw, a photodetectiondevices halts the stimulus and the timer. A maximal cut-off time of 40seconds is used to prevent tissue damage. Paw withdrawal latencies arethus determined to the nearest 0.1 second. The withdrawal latency ofsham-operated rats is compared to those of nerve-ligated rats to measurethe degree of hyperalgesia.

[0059] In addition, non-operated rats can be evaluated for centralsensitization arising from a tonic nociceptive stimulus, such asformalin injection in to the hindpaw. For this evaluation, non-operatedrats are allowed to acclimate to a flinching chamber for about 20minutes. A flinching chamber comprises wood panels with Plexiglas floorsand front panels to allow observation of the animal. A mirror is placedat about a 45° angle under the floor to facilitate viewing of theanimal's hindpaws. The rats are given a subcutaneous injection of 50 μlof 2% formalin solution s.c. into the dorsum of the right hindpawimmediately after administration of the vehicle or test article. Animalsare then returned to the flinching chambers for the duration of theexperiment and observed for flinching behavior. Numbers of flinchesobserved are recorded in 5 minute intervals for 50 minutes beginning atthe time of formalin injection. Data are recorded as mean flinches/5minute bin for phase I (0 to 15 minutes) and phase II (20 to 50minutes). The areas under the time-effect curves are calculated for eachrat to allow statistical analyses.

5.4. Example 4 Evaluation of Tinnitus

[0060] Hamsters and rats experience major increases in spontaneousneural activity in the dorsal cochlear nucleus (“DCN”) after exposure toagents known to induce tinnitus in humans, and thus may be used intinnitus animal models. See, e.g., Zhang and Kaltenbach, NeuroscienceLetters, 250(3) (1998); Kaltenbach et al., Hearing Res., 124(1-2):78-84(1998); and Meleca et al., Brain Res., 750(1-2):201-213 (1997). Thisincreased activity in the DCN displays a similar pattern to thatexhibited by sound-evoked DCN activity, and suggests that the animalswith agent-induced abnormality may be hearing a sound. See Kaltenbachand McCaslin, Auditory Neuroscience, 3/1:57-78 (1996). The effect ofR(−)-ketoprofen on tinnitus can be evaluated by determining its affecton reversing the increase in spontaneous DCN activity in rats orhamsters.

[0061] In general, changes in spontaneous activity in the DCN isperformed by exposing one ear (e.g., the left ear) of each animal to anintense 10 kHz tone at a level of 125 dB for a period of about 4 hours.After exposure, the animals are allowed to recover for about 4 weeks topermit stabilization of the induced increase in spontaneous DCNactivity. After this recovery period, each animal is anesthetized andundergoes surgery to uncover the DCN ipsilateral to the exposed ear.Thereafter, a microelectrode is used to map the activity along the DCNsurface. When the mapping is finished, the microelectrode is insertedinto the DCN at the location which shows the highest increase inactivity. The microelectrode is inserted to a depth of between about 130microns to about 200 microns, and the activity at this test site ismeasure to give a baseline spontaneous rate.

[0062] After the baseline measurement is taken, R(−)-ketoprofen, oranother test article or vehicle, is applied and the activity is thenmeasured to give a drug-related change in DCN activity. The effect ofthe drug is determined by the difference between pre- andpost-application activity measurements. After application of the testarticle and measurement of activity, the applied test article isaspirated off the surface of the DCN and an ACSF rinse or washoutsolution is applied. This same site is then tested with the same testarticle at several different concentrations, and the effect of the testarticle is again determined by taking the difference between pre- andpost-application spontaneous DCN activity rates.

5.5. Example 5 Oral Formulation

[0063] Table 1 provides the ingredients for a tablet dosage form ofoptically pure R(−)-ketoprofen: TABLE 1 Component Quantity per Tablet(mg) R(-)-ketoprofen 75 Lactose 125 Corn Starch 5.0 Water (per thousandtablets) 30.0 ml * Magnesium Stearate 0.5

[0064] The active ingredient (i.e., R(−)-ketoprofen) is blended with thelactose until a uniform blend is formed. The smaller quantity of cornstarch is blended with a suitable quantity of water to form a cornstarch paste. This is then mixed with the uniform blend until a uniformwet mass is formed. The remaining corn starch is added to the resultingwet mass and mixed until uniform granules are obtained. The granules arethen screened through a suitable milling machine, using a ¼ inchstainless steel screen. The milled granules are then dried in a suitabledrying oven until the desired moisture content is obtained. The driedgranules are then milled through a suitable milling machine using ¼ meshstainless steel screen. The magnesium stearate is then blended and theresulting mixture is compressed into tablets of desired shape,thickness, hardness and disintegration. Tablets are coated by standardaqueous or nonaqueous techniques.

[0065] Another tablet dosage formulation suitable for use with theactive ingredient of the invention is provided by Table 2: TABLE 2Quantity per Tablet (mg) Component Formula A Formula B Formula CR(-)-ketoprofen 20 40 100 Lactose BP 134.5 114.5 309.0 Starch BP 30 3060 Pregelatinized Maize Starch BP 15 15 30 Magnesium Stearate 0.5 0.51.0 Compression Weight 200 200 500

[0066] The active ingredient is sieved and blended with lactose, starch,and pregelatinized maize starch. Suitable volumes of purified water areadded and the powders are granulated. After drying, the granules arescreened and blended with the magnesium stearate. The granules are thencompressed into tablets using punches.

[0067] Tablets of other strengths may be prepared by altering the ratioof active ingredient to pharmaceutically acceptable carrier, thecompression weight, or by using different punches.

5.6. Example 6 Oral Formulation

[0068] Capsules of R(−)-ketoprofen suitable for the treatment ofneuropathic pain or tinnitus are made using the ingredients provided inTable 3: TABLE 3 Quantity per Capsule (mg) Formulation A B C IngredientsR(-)-ketoprofen 50.0 100.0 200.0 Lactose 48.5 148.5 48.5 TitaniumDioxide 0.5 0.5 0.5 Magnesium Stearate 1.0 1.0 1.0 Fill Weight 100.0250.0 250.0

[0069] The active ingredient (i.e., R(−)-ketoprofen) is sieved andblended with the excipients. The mixture is filled into suitably sizedtwo-piece hard gelatin capsules using suitable machinery. Other dosesmay be prepared by altering the ratio of R(−)-ketoprofen andpharmaceutically acceptable carrier, the fill weight and, if necessary,by changing the capsule size to suit.

[0070] The embodiments of the invention described above are intended tobe merely exemplary, and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A method of treating neuropathic pain in a mammalwhich comprises administering to a mammal in need of such treatment atherapeutically effective amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof.
 2. The method of claim 1 wherein the therapeuticallyeffective amount of substantially optically pure R(−)-ketoprofen, or apharmaceutically acceptable salt, solvate, or clathrate thereof, isbetween about 1 mg and about 2000 mg.
 3. The method of claim 2 whereinthe therapeutically effective amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 5 mg and about 1500 mg.
 4. Themethod of claim 3 wherein the therapeutically effective amount ofsubstantially optically pure R(−)-ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, is between about 10 mgand about 1000 mg.
 5. The method of claim 1 wherein the substantiallyoptically pure R(−)-ketoprofen comprises less than about 10% by weightS(+)-ketoprofen.
 6. The method of claim 5 wherein the substantiallyoptically pure R(−)-ketoprofen comprises less that about 5% by weightS(+)-ketoprofen.
 7. The method of claim 6 wherein the substantiallyoptically pure R(−)-ketoprofen comprises less than about 1% by weightS(+)-ketoprofen.
 8. The method of claim 1 wherein the neuropathic painis a central neuropathy.
 9. The method of claim 8 wherein the centralneuropathy arises from damage or disease of the spinal cord, brainstem,thalamus, or cerebellum.
 10. The method of claim 1 wherein theneuropathic pain is a peripheral neuropathy.
 11. The method of claim 10wherein the peripheral neuropathy is a thoracic outlet obstructionsyndrome, a compression and entrapment neuropathy, or Guillain-Barrésyndrome.
 12. The method of claim 11 wherein the compression andentrapment neuropathy is selected from the group consisting of ulnarnerve palsey, carpal tunnel syndrome, peroneal nerve palsey, and radialnerve palsey.
 13. The method of claim 1 wherein the mammal is human. 14.A pharmaceutical composition for the treatment of a mammal sufferingfrom neuropathic pain which comprises an amount of substantiallyoptically pure R(−)-ketoprofen or a pharmaceutically acceptable salt,solvate, or clathrate thereof, said amount being sufficient to alleviateat least one symptom of neuropathic pain.
 15. The pharmaceuticalcomposition of claim 14 further comprising a pharmaceutically acceptablecarrier.
 16. The pharmaceutical composition of claim 15 wherein thepharmaceutically acceptable carrier is solid.
 17. The pharmaceuticalcomposition of claim 14 wherein the amount of substantially opticallypure R(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 1 mg and about 2000 mg.
 18. Thepharmaceutical composition of claim 17 wherein the amount ofsubstantially optically pure R(−)-ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, is between about 5 mgand about 1500 mg.
 19. The pharmaceutical composition of claim 18wherein the amount of substantially optically pure R(−)-ketoprofen, or apharmaceutically acceptable salt, solvate, or clathrate thereof, isbetween about 10 mg and about 1000 mg.
 20. The pharmaceuticalcomposition of claim 14 wherein the substantially optically pureR(−)-ketoprofen comprises less than about 10% by weight S(+)-ketoprofen.21. The pharmaceutical composition of claim 20 wherein the substantiallyoptically pure R(−)-ketoprofen comprises less that about 5% by weightS(−)-ketoprofen.
 22. The pharmaceutical composition of claim 21 whereinthe substantially optically pure R(−)-ketoprofen comprises less thanabout 1% by weight S(+)-ketoprofen.
 23. A single unit dosage form forthe treatment of a mammal suffering from neuropathic pain whichcomprises substantially optically pure R(−)-ketoprofen, or apharmaceutically acceptable salt, solvate, or clathrate thereof, in anamount of between about 1 mg and about 2000 mg.
 24. The dosage form ofclaim 23 wherein the amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 5 mg and about 1500 mg.
 25. Thedosage form of claim 24 wherein the amount of substantially opticallypure R(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 10 mg and about 1000 mg.
 26. Thedosage form of claim 23 which is formulated for oral administration. 27.The dosage form of claim 26 which is solid.
 28. A method of treatingtinnitus or ringing in the ear in a patient which comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of substantially optically pure R(−)-ketoprofen, or apharmaceutically acceptable salt, solvate, or clathrate thereof.
 29. Themethod of claim 28 wherein the tinnitus or ringing in the ear isassociated with a disease or condition selected from the groupconsisting of: obstruction of the external auditory canal; infectiousprocesses including external otitis, myrignitis, otitis media,labyrinthitis, petrositis, syphilis and meningitis; eustachian tubeobstruction; otosclerosis; middle ear neoplasms such as the glomustympanicum and glomus jugulare tumors; Meniere's disease; arachnoiditis;cerebellopontine angle tumors; cardiovascular diseases includinghypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism;hereditary sensorineural or noise-induced hearing loss; acoustic trauma;ototoxicity caused by acute intoxication or long-term administration orexposure to drugs or toxins including salicylates, quinine and itssynthetic analogues, aminoglycoside antibiotics, diuretics, carbonmonoxide, and heavy metals; and psychological disorders.
 30. A method ofpreventing tinnitus or ringing in the ear in a patient at risk oftinnitus which comprises administering to said patient a therapeuticallyeffective amount of substantially optically pure R(−)-ketoprofen, or apharmaceutically acceptable salt, solvate, or clathrate thereof.
 31. Themethod of claim 28 or 30 wherein the therapeutically effective amount ofsubstantially optically pure R(−)-ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, is between about 1 mgand about 2000 mg.
 32. The method of claim 31 wherein thetherapeutically effective amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 5 mg and about 1500 mg.
 33. Themethod of claim 32 wherein the therapeutically effective amount ofsubstantially optically pure R(−)-ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, is between about 10 mgand about 1000 mg.
 34. The method of claim 28 or 30 wherein thesubstantially optically pure R(−)-ketoprofen comprises less than about10% by weight S(+)-ketoprofen.
 35. The method of claim 34 wherein thesubstantially optically pure R(−)-ketoprofen comprises less that about5% by weight S(+)-ketoprofen.
 36. The method of claim 35 wherein thesubstantially optically pure R(−)-ketoprofen comprises less than about1% by weight S(+)-ketoprofen.
 37. A pharmaceutical composition for thetreatment of a patient suffering from tinnitus which comprises an amountof substantially optically pure R(−)-ketoprofen or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, said amount beingsufficient to alleviate at least one symptom of tinnitus.
 38. Thepharmaceutical composition of claim 37 wherein the amount ofsubstantially optically pure R(−)-ketoprofen, or a pharmaceuticallyacceptable salt, solvate, or clathrate thereof, is between about 1 mgand about 2000 mg.
 39. The pharmaceutical composition of claim 38wherein the amount of substantially optically pure R(−)-ketoprofen, or apharmaceutically acceptable salt, solvate, or clathrate thereof, isbetween about 5 mg and about 1500 mg.
 40. The pharmaceutical compositionof claim 39 wherein the amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 10 mg and about 1000 mg.
 41. Asingle unit dosage form for the treatment of a patient suffering fromtinnitus which comprises substantially optically pure R(−)-ketoprofen,or a pharmaceutically acceptable salt, solvate, or clathrate thereof, inan amount of between about 1 mg and about 2000 mg.
 42. The dosage formof claim 41 wherein the amount of substantially optically pureR(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 5 mg and about 1500 mg.
 43. Thedosage form of claim 42 wherein the amount of substantially opticallypure R(−)-ketoprofen, or a pharmaceutically acceptable salt, solvate, orclathrate thereof, is between about 10 mg and about 1000 mg.
 44. Acomposition comprising R(−)-ketoprofen and a pharmaceutically acceptablecarrier.